The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1

Mathias Jenal; Emmanuelle Trinh; Christian Britschgi; Adrian Britschgi; Vincent Roh; Stephan A Vorburger; Andreas Tobler; Dominique Leprince; Martin F Fey; Kristian Helin; Mario P Tschan

doi:10.1158/1541-7786.MCR-08-0359

The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1

Mathias Jenal, Emmanuelle Trinh, Christian Britschgi, Adrian Britschgi, Vincent Roh, Stephan A Vorburger, Andreas Tobler, Dominique Leprince, Martin F Fey, Kristian Helin, Mario P Tschan

22 Citations (Scopus)

Abstract

The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses.

Original language	English
Journal	Molecular Cancer Research
Volume	7
Issue number	6
Pages (from-to)	916-22
Number of pages	6
ISSN	1541-7786
DOIs	https://doi.org/10.1158/1541-7786.MCR-08-0359
Publication status	Published - 2009

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@article{c57a6660625c11de8bc9000ea68e967b,

title = "The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1",

abstract = "The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses.",

author = "Mathias Jenal and Emmanuelle Trinh and Christian Britschgi and Adrian Britschgi and Vincent Roh and Vorburger, {Stephan A} and Andreas Tobler and Dominique Leprince and Fey, {Martin F} and Kristian Helin and Tschan, {Mario P}",

year = "2009",

doi = "10.1158/1541-7786.MCR-08-0359",

language = "English",

volume = "7",

pages = "916--22",

journal = "Molecular Cancer Research",

issn = "1541-7786",

publisher = "American Association for Cancer Research (A A C R)",

number = "6",

}

TY - JOUR

T1 - The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1

AU - Jenal, Mathias

AU - Trinh, Emmanuelle

AU - Britschgi, Christian

AU - Britschgi, Adrian

AU - Roh, Vincent

AU - Vorburger, Stephan A

AU - Tobler, Andreas

AU - Leprince, Dominique

AU - Fey, Martin F

AU - Helin, Kristian

AU - Tschan, Mario P

PY - 2009

Y1 - 2009

N2 - The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses.

AB - The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses.

U2 - 10.1158/1541-7786.MCR-08-0359

DO - 10.1158/1541-7786.MCR-08-0359

M3 - Journal article

C2 - 19491197

SN - 1541-7786

VL - 7

SP - 916

EP - 922

JO - Molecular Cancer Research

JF - Molecular Cancer Research

IS - 6

ER -

The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1

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